tbuckley/cabot-search huggingface dataset:
Abstract LB138: DAXX interacts with sterol regulatory element-binding proteins (SREBPs) to promote oncogenic lipogenesis and tumorigenesis in triple-negative breast cancer
Authors: Iqbal Mahmud, Guimei Tian, Tarun Hutchison, Brandon Kim, Daiqing Liao
Journal: Cancer Research (2022)

Abstract Elevated lipid metabolism including lipogenesis is a major metabolic feature in cancer cells. In breast and other cancer types, genes involved in lipogenesis are highly upregulated, but the mechanisms that control their expression remain poorly understood. DAXX modulates gene expression through binding to numerous transcription factors although the functional impact of these diverse interactions remains to be defined. Our recent analysis indicates that DAXX is overexpressed in diverse cancer types and metastases. However, mechanisms underlying DAXX’s oncogenic function remains elusive. Using global integrated transcriptomic and lipidomic analyses, we show that DAXX plays a key role in lipid metabolism in triple-negative breast cancer (TNBC) cells. DAXX depletion attenuates, while its overexpression enhances, lipogenic gene expression, lipid synthesis and tumor growth. Mechanistically, DAXX interacts with SREBP1 and SREBP2 and activates SREBP-mediated transcription. DAXX associates with lipogenic gene promoters through SREBPs. Underscoring the critical roles for the DAXX-SREBP interaction for lipogenesis, SREBP2 knockdown attenuates tumor growth in cells with DAXX overexpression, and a DAXX mutant unable to bind SREBPs are incapable of promoting lipogenesis and tumor growth. In TNBC patients, DAXX expression levels are increased in breast cancer brain metastasis and correlate with poor patient survival. Our results identify the DAXX-SREBP axis as an important pathway for tumorigenesis in TNBC. (This work is supported by Florida Department of Health Grants.) Citation Format: Iqbal Mahmud, Guimei Tian, Tarun Hutchison, Brandon Kim, Daiqing Liao. DAXX interacts with sterol regulatory element-binding proteins (SREBPs) to promote oncogenic lipogenesis and tumorigenesis in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB138.
Clinical Examination of the Hip
Authors: Jordan R. Pollock, M. Lane Moore, Kade S. McQuivey, Justin L. Makovicka, Kostas Economopoulos, Joshua S. Bingham
Journal: New England Journal of Medicine (2022)

Hip pain is common, and the hip joint is complex. Obtaining a relevant patient history and conducting a proper physical examination can be challenging. This video demonstrates how to assess a patient with hip pain.
Abstract 2568: ARTS-021 is a potent and selective CDK2 inhibitor that demonstrates anti-cancer activity in preclinical cancer models with CCNE1 amplification
Authors: jiaqi Liang, Dai Cheng, Yali Guo, xiaobin zhang, Xipan Liu, Jia Fu, Qiang Ding, Wen Xiong, Fang Li, Yaoyu Chen, Qing Sheng
Journal: Cancer Research (2022)

Abstract Cyclin E1 amplification is prevalent in cancers with high unmet medical need such as high grade serous ovarian cancer, stomach cancer and esophageal cancer. Cancer cell lines with high expression level of cyclin E1 gene exhibited profound sensitivity to CDK2 gene depletion, suggesting CDK2 selective inhibitors have the potential to treat patients harboring Cyclin E1 alterations. Here we report the development and preclinical characterization of ARTS-021, an orally bioavailable small molecule CDK2 selective inhibitor. In enzymatic assay against a panel of different CDKs, ARTS-021 potently inhibits the activity of CDK2/CyclinE1 complex with 50% inhibitory concentration (IC50) in the sub-nanomolar range, displaying superior selectivity against other CDKs (CDK1,4,6,7,9). Very low hit rate (S(10)=0.022, at 1uM) is observed when ARTS-021 is assessed in whole Kinome profiling, further revealing the selectivity of this compound. ARTS-021 also demonstrates potent CDK2 inhibition and selectivity against other CDK family members (CDK1,4,6,9) in a series of cellular assays. Consistent with genetic CDK2 dependence data, cell lines with CCNE1 amplification are particularly sensitive to ARTS-021. Double nanomolar ARTS-021 inhibits Rb phosphorylation and blocks G1/S transition, leading to cell growth arrest specifically in CCNE1 amplified cell lines. This CDK2 dependent anti-tumor activity is further validated in vivo, where daily ARTS-021 administration leads to tumor stasis in CCNE1 amplified but not wild type xenograft models. Taken together, these data demonstrate ARTS-021 as a promising CDK2 selective inhibitor with strong potential towards the development of effective therapies for CCNE1 altered cancer. Citation Format: jiaqi Liang, Dai Cheng, Yali Guo, xiaobin zhang, Xipan Liu, Jia Fu, Qiang Ding, Wen Xiong, Fang Li, Yaoyu Chen, Qing Sheng. ARTS-021 is a potent and selective CDK2 inhibitor that demonstrates anti-cancer activity in preclinical cancer models with CCNE1 amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2568.
Abstract 1319: Complement activation in pancreatic ductal adenocarcinoma
Authors: Brett I. Bell, Sanjay Pandey, Patrik Asp, Chandan Guha
Journal: Cancer Research (2022)

Abstract The complement system is an innate immune cascade which recognizes and clears microbes and damaged host cells. Complement activation has been linked to the promotion of tumor growth and metastasis across various anatomical sites with context-dependent effects. We therefore aim to understand the role for complement activation in pancreatic cancer. We have generated a tamoxifen-inducible autochthonous mouse model of PDAC which recapitulates genetic mutations found in humans using LSL-KrasG12D/+; Tgfbr2fl/fl; Ptf1a-CreER (KTC) mice. Using these mice, we assessed for complement activation in pancreatic tumors by western blot and confocal immunofluorescence. Western blotting for neoepitopes generated upon cleavage of Complement Component 3 (C3) demonstrated significantly increased complement activation in KTC tumors when compared to normal pancreas from at least 4-7 months post-induction. Using confocal immunofluorescence, we observed deposition of complement fragments in tumor stroma and on ductal carcinoma cells identified by co-staining with cytokeratin 19. We therefore hypothesized complement blockade would reduce PDAC tumor growth and sought to test this using C3 knockout (C3 KO) mice which lack all downstream complement function due to the central role of C3. We assessed flank tumor growth using two Kras; Tp53 (KPC) mutant-derived tumor cell lines in wild type (WT) C57BL/6J and C3 KO mice yet did not find a biologically significant reduction in flank tumor growth between WT and C3 KO. To validate the knockout, we assessed C3 activation by western blot but surprisingly found increased complement activation in C3 KO tumors. RT-qPCR demonstrated local transcription of C3 mRNA in both WT and C3 KO tumors as well as transcription of C3 mRNA in KPC cells in culture. This demonstrates that KPC cells are capable of autocrine production of C3. Using immunocytochemistry and RT-qPCR we identified expression of the C3a receptor in KPC cells which we hypothesized could serve as a sensor for feedback to control local C3 production. We applied 10 nM recombinant C3a to KPCY cells in vitro and found a 20% reduction in C3 mRNA transcription 1-hour post-treatment. Pre-treatment with 500 nM C3aR Antagonist (SB290157) ablated this effect. In summary, complement activation is significantly increased in PDAC and appears to be activated in part by tumor cells themselves. Autocrine production of C3 by tumor cells is sufficient to produce complement activation in the absence of systemic C3. Additional experiments are warranted to determine the role of complement in PDAC using C3 mice crossed with KTC mice to assess tumorigenesis in the total absence of C3. Citation Format: Brett I. Bell, Sanjay Pandey, Patrik Asp, Chandan Guha. Complement activation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1319.
Abstract 4240: <i>In vivo</i> assessment of AICD and cytokine release upon treatment of OKT3 and CD3 bispecific antibody in homozygous CD3EDG HuGEMM™
Authors: Daniel XF He
Journal: Cancer Research (2022)

Abstract Introduction: CD3 bispecific antibodies have transformed the therapeutic landscape of immunotherapy for some hematological malignancies, however, the clinical therapeutic effects of CD3 bispecific therapies is still under investigation for solid tumors. Moreover, CD3 bispecific antibody-mediated tumor targeting as well as T cell engagement have resulted in cytokine release syndrome (CRS), increased on-target/off-tumor toxicities and poor T cell infiltration, which may affect safety and limit therapeutic efficacy. To better understand the relationship between T cell activation and systemic cytokine release in the context of CD3 bispecific antibody treatment, a homozygous human CD3EDG HuGEMM࣪ preclinical model was developed. Methods: The homozygous CD3EDG HuGEMM mice, which express human CD3ε/CD3δ/CD3γ on the surface of T cells, were subcutaneously inoculated with MC38 or MC38-hEpCAM HuCELL™ syngeneic tumors and treated with vehicle, anti-mPD-1 (RMP1-14), OKT3, and anti-hCD3×hEpCAM. For efficacy studies, mouse body weight and tumor volume were measured twice weekly and tumor growth inhibition (TGI%) was determined. To investigate OKT3 or CD3 bispecifics-induced cytokine release, mouse body weight was monitored daily and several inflammatory and proinflammatory cytokines in the serum were detected by MSD. Results: Firstly, anti-mPD-1 treatment (5 mg/kg and 15 mg/kg i.p.) of homozygous CD3EDG mice engrafted with MC38 syngeneic tumors led to 42% and 62% TGI, respectively. OKT3 treatment of MC38-hEpCAM bearing homozygous CD3EDG HuGEMM promoted tumor growth (TGI= -80%), likely due to activation-induced cell death (AICD) of T cells. In addition, CRS was induced within 24 hours of OKT3 dosing, with IL-2, IL-6, and TNF-α peaking 2 hr post the 1st dose, and IFN-γ, IL-10 and IL-5 peaking 6 hr post the 1st dose. In contrast, no significant cytokine release was observed upon anti-hCD3×hEpCAM treatment despite remarkable TGI, indicating that the delicate balance of in vivo T cell activation and T cell cytotoxicity is crucial for effective tumor killing by CD3 bispecific antibodies or engagers. Conclusions: Our CD3EDG HuGEMM and HuCELL models provide a predictive platform for in vivo efficacy and safety assessment of CD3 bispecific or trispecific antibodies. The uncoupling of systemic cytokine release and T cell cytotoxicity via CD3 bispecific or trispecific antibodies provides a biological rationale to clinically explore preventative treatment approaches to avoid or reduce CRS-related toxicity, as well as combination approaches to increase selectivity and efficacy. Citation Format: Daniel XF He. In vivo assessment of AICD and cytokine release upon treatment of OKT3 and CD3 bispecific antibody in homozygous CD3EDG HuGEMM™ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4240.
Synthetic growth hormone-releasing hormone agonist ameliorates the myocardial pathophysiology characteristic of heart failure with preserved ejection fraction
Authors: Raul A Dulce, Rosemeire M Kanashiro-Takeuchi, Lauro M Takeuchi, Alessandro G Salerno, Amarylis C B A Wanschel, Shathiyah Kulandavelu, Wayne Balkan, Marilia S S R Zuttion, Renzhi Cai, Andrew V Schally, Joshua M Hare
Journal: Cardiovascular Research (2022)

To test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signalling pathway within the myocardium both prevents and reverses diastolic dysfunction and pathophysiologic features consistent with heart failure with preserved ejection fraction (HFpEF). Impaired myocardial relaxation, fibrosis, and ventricular stiffness, among other multi-organ morbidities, characterize the phenotype underlying the HFpEF syndrome. Despite the rapidly increasing prevalence of HFpEF, few effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, cardiomyocyte hypertrophy, and improve performance in animal models of ischaemic cardiomyopathy, independently of the growth hormone axis.CD1 mice received 4- or 8-week continuous infusion of angiotensin-II (Ang-II) to generate a phenotype with several features consistent with HFpEF. Mice were administered either vehicle or a potent synthetic agonist of GHRH, MR-356 for 4-weeks beginning concurrently or 4-weeks following the initiation of Ang-II infusion. Ang-II-treated animals exhibited diastolic dysfunction, ventricular hypertrophy, interstitial fibrosis, and normal ejection fraction. Cardiomyocytes isolated from these animals exhibited incomplete relaxation, depressed contractile responses, altered myofibrillar protein phosphorylation, and disturbed calcium handling mechanisms (ex vivo). MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. Activation of the GHRH receptors increased cAMP and cGMP in cardiomyocytes isolated from control animals but only cAMP in cardiac fibroblasts, suggesting that GHRH-A exert differential effects on cardiomyocytes and fibroblasts.These findings indicate that the GHRH receptor signalling pathway(s) represents a new molecular target to counteract dysfunctional cardiomyocyte relaxation by targeting myofilament phosphorylation and fibrosis. Accordingly, activation of GHRH receptors with potent, synthetic GHRH agonists may provide a novel therapeutic approach to management of the myocardial alterations associated with the HFpEF syndrome.
Effects of Previous Infection and Vaccination on Symptomatic Omicron Infections
Authors: Heba N. Altarawneh, Hiam Chemaitelly, Houssein H. Ayoub, Patrick Tang, Mohammad R. Hasan, Hadi M. Yassine, Hebah A. Al-Khatib, Maria K. Smatti, Peter Coyle, Zaina Al-Kanaani, Einas Al-Kuwari, Andrew Jeremijenko, Anvar H. Kaleeckal, Ali N. Latif, Riyazuddin M. Shaik, Hanan F. Abdul-Rahim, Gheyath K. Nasrallah, Mohamed G. Al-Kuwari, Adeel A. Butt, Hamad E. Al-Romaihi, Mohamed H. Al-Thani, Abdullatif Al-Khal, Roberto Bertollini, Laith J. Abu-Raddad
Journal: New England Journal of Medicine (2022)

The protection conferred by natural immunity, vaccination, and both against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with the BA.1 or BA.2 sublineages of the omicron (B.1.1.529) variant is unclear.
Abstract 2652: Efficacy of a small molecule MCT1 and MCT4 transporter inhibitor in cancer
Authors: Sambad Sharma, Gregory Goreczny, Nicole Bowman, Jennifer Duffy, Daliya Banerjee, Sanath Wijerathna, John Dzuris, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, Kounosuke Watabe, Jaime Escobedo, Vincent Sandanayaka
Journal: Cancer Research (2022)

Abstract Targeting metabolic pathways has been a major clinical interest to effectively treat cancer patients. FDA approval of TIVSOVO(R) (IDH1 inhibitor) has validated the clinical importance of targeting tumor metabolism in cancer. Although MCT1-targeting small molecule inhibitor is currently under investigation for lymphoid cancers, the therapeutic efficacy of this compound is compromised by compensatory overexpression of MCT4 by tumor cells. Therefore, there is a need for a dual MCT1/4 inhibitor to target cancer. We have developed a first-in-class orally bioavailable small molecule inhibitor that targets lactate transport through MCT1 and MCT4 transporters. In 4T1 syngeneic model, we observed a significant dose-dependent reduction of tumor growth by NGY-B treatment that also correlated with serum lactate levels. Immunoprofiling of tumors revealed that NGY-B promoted anti-tumor immune response in 4T1 tumor bearing mice indicating simultaneous immune activation. Also, the combination of NGY-B with a checkpoint inhibitor led to greater efficacy and overall survival in this model suggesting a potential combination therapy in the clinic. Furthermore, we demonstrated the direct tumor cell killing effect of NGY-B in multiple human CDX and PDX models. Therefore, NGY-B intervenes two key hallmarks of cancer - tumor metabolism and anti-tumor immunity, and provides a novel modality to therapeutically target cancer. Citation Format: Sambad Sharma, Gregory Goreczny, Nicole Bowman, Jennifer Duffy, Daliya Banerjee, Sanath Wijerathna, John Dzuris, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, Kounosuke Watabe, Jaime Escobedo, Vincent Sandanayaka. Efficacy of a small molecule MCT1 and MCT4 transporter inhibitor in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2652.
Abstract 679: Inhibition of Notch signaling causes progenitor-to-hepatocyte differentiation and regressions in a subset of hepatocellular carcinoma by controlling C/EBPα expression and HNF4α activity
Authors: Kerstin Seidel, Robert Piskol, Thi Thu Thao Nguyen, Charisa Cottonham, Mark Merchant, Christian Siebel
Journal: Cancer Research (2022)

Abstract ​​Notch signaling regulates cell fate decisions during development and maintenance of many organs. During hepatogenesis, an active NOTCH2 signal is required for specification of the cholangiocyte lineage, while hepatoblasts remaining in a Notch-off state contribute to the default hepatocyte lineage. Notch pathway activation has been reported in liver tumors, although Notch-related liver cancer mutations are rare. We identified a subset of hepatocellular carcinoma that is exceptionally sensitive to the inhibition of a JAG1-NOTCH2 signal in a mouse preclinical trial using 47 liver cancer PDX models. Transcriptional profiling revealed that the sensitive models resemble a progenitor-like state. Highly selective therapeutic antibodies targeting either the JAG1 ligand or the NOTCH2 receptor triggered hepatocyte differentiation programs and tumor regressions.Single cell analyses revealed heterogeneous transcriptional states at baseline, some of which were profoundly perturbed upon Notch inhibition. Topic modeling combined with inference of transcription factor activities suggested the involvement of HNF4α and C/EBPα in treatment induced changes. Through its target HES1, Notch signaling directly represses C/EBPα expression. Notch inhibition derepresses C/EBPα which then binds chromatin in cooperation with HNF4α. We found that this cooperative binding results in expression of genes associated with mature hepatocyte activity, which was incompatible with tumor maintenance. Importantly, we identify hallmarks to aid the identification of this relatively rare tumor type. We suggest that inducing cell states towards differentiated, less aggressive states, especially using targeted single-agent therapeutics, holds great promise for the treatment of certain tumors in the liver and, by extension, possibly in other progenitor-like cancers. Citation Format: Kerstin Seidel, Robert Piskol, Thi Thu Thao Nguyen, Charisa Cottonham, Mark Merchant, Christian Siebel. Inhibition of Notch signaling causes progenitor-to-hepatocyte differentiation and regressions in a subset of hepatocellular carcinoma by controlling C/EBPα expression and HNF4α activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 679.
Abstract 1717: Single-cell RNA sequencing reveals insights into the intra-tumoral heterogeneity and tumor microenvironment of ocular adnexal sebaceous carcinoma
Authors: Ryan Alexander Gallo, Michelle G. Zhang, David T. Tse, Daniel Pelaez, Andrew J. Rong
Journal: Cancer Research (2022)

Abstract Sebaceous carcinoma (SC) is a malignant neoplasm that predominantly arises from the sebaceous glands of the ocular adnexa. It is the second most common malignant eyelid neoplasm in the United States. No standardized treatment exists, but surgical excision is the mainstay of therapy. Therapeutic advances have been stagnant largely due to a limited understanding of SC tumor biology. We performed single-cell RNA sequencing to profile primary ocular adnexal SC and gain insights into its tumor microenvironment. Ocular adnexal SC has extensive intra-tumoral heterogeneity at the transcriptional level. Dimensionality reduction via principal component analysis was performed to identify major cell types. 8 clusters were detected, including clusters for cancer epithelial cells and various immune cells. Transcriptional programs were related to pathways in cancer, immune response, and antigen processing and processing, among others. We identified unique subpopulations of tumor-infiltrating immune cells, including plasma B cells, GNLY+ natural killer cells, CD8+ T cells, memory T cells, and CD20+ B cells. This complex ecosystem of tumor and immune cells provides new insights into SC biology. Additional patient samples we be analyzed in the immediate future. Follow-up mechanistic studies are needed to clarify the roles of the identified immune cells and how they can be exploited for immunotherapeutic approaches. Citation Format: Ryan Alexander Gallo, Michelle G. Zhang, David T. Tse, Daniel Pelaez, Andrew J. Rong. Single-cell RNA sequencing reveals insights into the intra-tumoral heterogeneity and tumor microenvironment of ocular adnexal sebaceous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1717.